Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia.

In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.

Two-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia.

We previously reported on the immediate safety and neonatal outcomes of six premature infants with severe bronchopulmonary dysplasia (BPD) who were administered human amnion epithelial cells (hAECs). One infant died in the neonatal period due to unrelated causes. In this study, we aimed to assess the long-term safety and follow-up outcomes of the five surviving infants until 2 years corrected age (CA). hAECs were administered intravenously at a dose of 1 × 106 cells per kilogram after 36 weeks postconceptional age in infants with established BPD. Study follow-up consisted of assessment of any adverse events, growth, and respiratory, cardiac, and neurodevelopmental outcomes over four time points (6, 12, 18, and 24 months CA). Investigations included chest x-rays, cranial and abdominal ultrasounds, and echocardiograms at regular intervals as well as a magnetic resonance imaging (MRI) brain at 2 years CA. All five infants were alive at 2 years CA. Median time to wean off oxygen was 24 (10-36) months. Two infants had pulmonary hypertension, which resolved by 2 years of age. Four infants were rehospitalized briefly for viral or bacterial infections during the 2 years. MRI brain findings included normal (n = 1), and mild to moderate white matter loss (n = 2). Neurodisabilities diagnosed included hemiplegic cerebral palsy (n = 1), global developmental delay (n = 3), and severe hearing loss (n = 3). No evidence of tumor formation was noted on physical examinations or on any imaging. There were no long-term adverse events observed that could be attributed to hAEC administration. We observed long-term effects of extreme prematurity and severe BPD in the cohort.

Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age. METHODS AND ANALYSES: We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety. ETHICS AND DISSEMINATION: This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants. TRIAL REGISTRATION NUMBER: ACTRN12617001515381; Pre-results.

Sulforaphane improves endothelial function and reduces placental oxidative stress in vitro.

INTRODUCTION: The maternal endothelial dysfunction characteristic of preeclampsia arises, in part, from excessive placental production of anti-angiogenic factors, including soluble Flt-1, soluble endoglin and activin A, inducing oxidative stress. We assessed whether the antioxidant and NRF2-activator sulforaphane could mitigate endothelial and trophoblast dysfunction in vitro. METHODS: We induced dysfunction in human umbilical vein endothelial cells (HUVECs) with TNF-α, assessing endothelial activation and dysfunction (endothelin-1, vascular cell adhesion molecule; VCAM1, intracellular adhesion molecule; ICAM1, e-selectin and endothelial permeability) in the presence or absence of sulforaphane. We also assessed the effects of sulforaphane in mitigating hypoxic and hyperoxic injury in term placental explants by measuring secretion of anti-angiogenic factors. To assess the role of NRF2 we silenced NRF2 in HUVECs and primary trophoblast cells. RESULTS: Sulforaphane reduced TNF-α mediated HUVEC secretion of endothelin-1, VCAM1, ICAM1 and E-selectin, and prevented increased endothelial permeability. In placental explants, sulforaphane reduced the secretion of soluble Flt-1, soluble endoglin and activin A. Sulforaphane induced activation and nuclear translocation of NRF2 in HUVECs, inducing heme oxygenase 1. NRF2 silencing blocked some but not all of sulforaphane's effects in HUVECs. NRF2 silencing did not prevent sulforaphane's inhibition of trophobast secretion of soluble Flt-1 or activin A. CONCLUSION: In reducing placental and endothelial oxidative stress, sulforaphane may offer a new adjuvant therapeutic approach for the treatment of preeclampsia.

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that mainly affects premature babies who require ventilator support. The pathogenesis of BPD is complex but includes vascular maldevelopment, alveolarization arrest, and lung inflammation. There is no cure for BPD. Clinical care is limited to supportive respiratory measures. A population of stem-like cells derived from placental membranes, human amnion epithelial cells (hAECs), has shown therapeutic promise in preclinical models of BPD. With a view to future efficacy trials, we undertook a first-in-human clinical trial of hAECs in babies with BPD to assess the safety of these cells. In a single-center, open-label phase I trial, we administered allogeneic hAECs (1 × 106 per kilogram bodyweight) by intravenous infusion to six premature babies with BPD. The primary outcomes of the study were focused on safety, including local site reaction, anaphylaxis, infection, features of rejection, or tumor formation. Outcomes to discharge from neonatal unit were studied. The hAECs were well tolerated. In the first baby, there was transient cardiorespiratory compromise during cell administration consistent with a pulmonary embolic event. Following changes to cell administration methods, including introduction of an inline filter, and reducing the cell concentration and the rate of cell infusion, no such events were observed in the subsequent five babies. We did not see evidence of any other adverse events related to cell administration. Allogeneic hAECs can be safely infused into babies with established BPD. Future randomized clinical trials to assess efficacy in this patient population are justified. Stem Cells Translational Medicine 2018;7:628-635.

EEG power spectrum maturation in preterm fetal growth restricted infants.

Power spectral analysis of the electroencephalogram (EEG) is a non-invasive method to examine infant brain maturation. Preterm fetal growth restricted (p-FGR) neonates display an altered EEG power spectrum compared to appropriate-for-gestational-age (AGA) peers, suggesting delayed brain maturation. Longitudinal studies investigating EEG power spectrum maturation in p-FGR infants are lacking, however. We thus aimed to investigate brain maturation using sleep EEG power spectral analysis in p-FGR infants compared to preterm and term AGA controls (p-AGA and t-AGA, respectively). EEG was recorded during spontaneous sleep in 13 p-FGR, 17 p-AGA and 19 t-AGA infants at 1 and 6 months post-term age. Infant sleep states (active and quiet sleep) were scored using standard criteria. Power spectral analysis of a single-channel EEG (C3-M2/C4-M1) was performed using Fast Fourier Transform. The EEG power spectrum was divided into delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), sigma (12-14 Hz) and beta (14-30 Hz) frequency bands. Relative (%) powers and the spectral edge frequency were calculated. The spectral edge frequency was significantly higher in p-FGR infants compared to p-AGA controls in quiet sleep at 1 month post-term age (p < .01). This was due to significantly reduced %-delta and significantly increased %-theta, %-alpha and %-beta power (p < .01 for all) compared to p-AGA infants. p-FGR infants also showed significantly increased %-beta power compared to t-AGA infants (p < .05). No group differences were observed in active sleep or at 6 months post-term age. In conclusion, p-FGR infants show altered sleep EEG power spectrum maturation compared to AGA peers. However, changes resolved by 6 months post-term age.

Role of Activin A in the Pathogenesis of Endothelial Cell Dysfunction in Preeclampsia.

This chapter describes the methodologies which may be used in evaluating in vitro endothelial cell dysfunction in preeclampsia.

Effects of foetal growth restriction and preterm birth on cardiac morphology and function during infancy.

AIM: To investigate the effects of foetal growth restriction (FGR) and prematurity on cardiac morphology and function in infancy. We hypothesised that FGR and prematurity would both alter cardiac development. METHODS: Cardiac morphology and function were evaluated in 24 preterm FGR infants (p-FGR) and 23 preterm and 19 term appropriately grown for gestational age infants (p-AGA and t-AGA, respectively) by conventional echocardiography and Tissue Doppler Imaging. p-FGR and p-AGA infants were studied on postnatal day 1 and all groups were studied at one-and six-months post-term age. RESULTS: p-FGR infants demonstrated increased cardiac sphericity compared to AGA peers on postnatal day 1 (p = 0.004) and at one-month post-term age (p = 0.004). Posterior and relative wall thickness increased overtime in the p-FGR group only (p < 0.05). Systolic function was not different between groups. E/e' ratio was higher in both preterm groups compared to the term group at one-month post-term age (p = 0.01). No statistically significant group differences were found at six-months post-term age. CONCLUSION: Foetal growth restriction was associated with subtle cardiac morphological changes, whereas both prematurity and FGR were associated with subclinical alterations in diastolic function.

Resveratrol mitigates trophoblast and endothelial dysfunction partly via activation of nuclear factor erythroid 2-related factor-2.

INTRODUCTION: Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation. METHOD: We used in vitro term placental explants to assess the effects of resveratrol on placental oxidative stress and production of sFlt1, sEng and activin A. Using human umbilical vein endothelial cells we investigated the effects of resveratrol on markers of in vitro endothelial dysfunction, including the expression of intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin and endothelin-1, and endothelial permeability. To confirm that resveratrol mediated its effects via Nrf2, we examined the impact of resveratrol on the same in vitro markers of endothelial and placental dysfunction following Nrf2 knockdown. RESULTS: Resveratrol significantly decreased placental oxidative stress and the production of sFlt1 and activin A. Resveratrol significantly mitigated tumor necrosis factor-α stimulated endothelial expression of ICAM1, VCAM1, E-selectin and endothelin-1 and prevented an increase in endothelial monolayer permeability. Nrf2 knockdown abolished some of the protective effects of resveratrol on endothelial cells, but not in primary trophoblast cells. CONCLUSION: Features of placental and endothelial dysfunction characteristic of preeclampsia are improved by resveratrol in vitro, partially via the modulation of Nrf2.

Creatine biosynthesis and transport by the term human placenta.

INTRODUCTION: Creatine is an amino acid derivative that is involved in preserving ATP homeostasis. Previous studies suggest an important role for the creatine kinase circuit for placental ATP turnover. Creatine is obtained from both the diet and endogenous synthesis, usually along the renal-hepatic axis. However, some tissues with a high-energy demand have an inherent capacity to synthesise creatine. In this study, we determined if the term human placenta has the enzymatic machinary to synthesise creatine. METHODS: Eleven placentae were collected following elective term caesarean section. Samples from the 4 quadrants of each placenta were either fixed in formalin or frozen. qPCR was used to determine the mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (SLC6A8). Protein expression of AGAT and GAMT was quantified by Western blot, and observations of cell localisation of AGAT, GAMT and SLC6A8 made with immunohistochemistry. Synthesis of guanidinoacetate (GAA; creatine precursor) and creatine in placental homogenates was determined via GC-MS and HPLC, respectively. RESULTS: AGAT, GAMT and SLC6A8 mRNA and protein were detected in the human placenta. AGAT staining was identified in stromal and endothelial cells of the fetal capillaries. GAMT and SLC6A8 staining was localised to the syncytiotrophoblast of the fetal villi. Ex vivo, tissue homogenates produce both GAA (4.6 nmol mg protein-1h-1) and creatine (52.8 nmol mg protein-1h-1). DISCUSSION: The term human placenta has the capacity to synthesise creatine. These data present a new understanding of placental energy metabolism.

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4.

Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC-derived proresolution lipoxin-A4 (LXA4) on T-cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin-induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T-cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC-treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T-cell suppression are LXA4 dependent, whereas the inhibition of neutrophil-derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid-based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4-dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085-1095.

Fetal-growth-restricted preterm infants display compromised autonomic cardiovascular control on the first postnatal day but not during infancy.

BackgroundFetal growth restriction (FGR) is associated with increased perinatal mortality and long-term cardiovascular and neurodevelopmental sequelae. We hypothesized that FGR impacts on the development of autonomic heart rate and blood pressure control, contributing to unfavorable short- and long-term outcomes following FGR.MethodsWe studied 25 preterm FGR and 22 preterm and 19 term appropriate for gestational age (AGA) infants. Preterm neonates were studied on postnatal day 1, and all infants were studied at 1 and 6 months post-term age. To investigate autonomic cardiovascular control, we examined heart rate variability (HRV) and baroreflex sensitivity using spectral power and transfer-function analyses.ResultsPreterm FGR neonates exhibited higher heart rates and reduced HRV compared with preterm AGA controls on postnatal day 1. No significant differences were found between the three groups at 1 or 6 months post-term age.ConclusionPreterm FGR neonates display compromised HRV on postnatal day 1, which may suggest increased vulnerability to circulatory instability. This may predispose these neonates to systemic and cerebral hypoperfusion and increase the risk of long-term neurodevelopmental sequelae. Differences were no longer found at 1 and 6 months post-term age, suggesting that the maturation of autonomic cardiovascular control may be preserved following FGR.

Human amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury.

BACKGROUND: Human amnion epithelial cells (hAECs) are clonogenic and have been proposed to reduce inflammatory-induced tissue injury. Perturbation of the immune response is implicated in the pathogenesis of perinatal brain injury; modulating this response could thus be a novel therapy for treating or preventing such injury. The immunomodulatory properties of hAECs have been shown in other animal models, but a detailed investigation of the effects on brain immune cells following injury has not been undertaken. Here, we investigate the effects of hAECs on microglia, the first immune responders to injury within the brain. METHODS: We generated a mouse model combining neonatal inflammation and perinatal hyperoxia, both of which are risk factors associated with perinatal brain injury. On embryonic day 16 we administered lipopolysaccharide (LPS), or saline (control), intra-amniotically to C57Bl/6 J mouse pups. On postnatal day (P)0, LPS pups were placed in hyperoxia (65% oxygen) and control pups in normoxia for 14 days. Pups were given either hAECs or saline intravenously on P4. RESULTS: At P14, relative to controls, LPS and hyperoxia pups had reduced body weight, increased density of apoptotic cells (TUNEL) in the cortex, striatum and white matter, astrocytes (GFAP) in the white matter and activated microglia (CD68) in the cortex and striatum, but no change in total microglia density (Iba1). hAEC administration rescued the decreased body weight and reduced apoptosis and astrocyte areal coverage in the white matter, but increased the density of total and activated microglia. We then stimulated primary microglia (CD45lowCD11b+) with LPS for 24 h, followed by co-culture with hAEC conditioned medium for 48 h. hAEC conditioned medium increased microglial phagocytic activity, decreased microglia apoptosis and decreased M1 activation markers (CD86). Stimulating hAECs for 24 h with LPS did not alter release of cytokines known to modulate microglia activity. CONCLUSIONS: These data demonstrate that hAECs can directly immunomodulate brain microglia, probably via release of trophic factors. This observation offers promise that hAECs may afford therapeutic utility in the management of perinatal brain injury.

Maternal Asian ethnicity and obstetric intrapartum intervention: a retrospective cohort study.

BACKGROUND: Maternal ethnicity is a recognized risk factor for stillbirth, such that South Asian women have higher rates than their Caucasian counterparts. However, whether maternal ethnicity is a risk factor for intrapartum outcomes is less clear. The aim of this study is to explore associations between maternal country of birth, operative vaginal delivery and emergency cesarean section, and to identify possible mechanisms underlying any such associations. METHODS: We performed a retrospective cohort study of singleton term births among South Asian, South East/East Asian and Australian/New Zealand born women at an Australian tertiary hospital in 2009-2013. The association between maternal country of birth, operative vaginal birth and emergency cesarean was assessed using multivariate logistic regression. RESULTS: Of the 31,932 births, 54% (17,149) were to Australian/New Zealand-born women, 25% (7874) to South Asian, and 22% (6879) to South East/East Asian born women. Compared to Australian/New Zealand women, South Asian and South East/East Asian women had an increased rate of both operative vaginal birth (OR 1.43 [1.30-1.57] and 1.22 [1.11-1.35] respectively, p < 0.001 for both) and emergency cesarean section (OR 1.67 [1.53-1.82] and 1.16 [1.04-1.26] respectively, p < 0.001 and p = 0.007 respectively). While prolonged labor was the predominant reason for cesarean section among Australian/New Zealand and South East/East Asian women, fetal compromise accounted for the majority of operative births in South Asian women. CONCLUSION: South Asian and South East/East Asian women experience higher rates of both operative vaginal birth and cesarean section in comparison to Australian/New Zealand women, independent of other risk factors for intrapartum interventions.

Customised management of the third stage of labour.

BACKGROUND: Postpartum haemorrhage (PPH) rates are increasing worldwide. The rate is particularly high in women undergoing an induced or augmented labour. In response to this, we altered our hospital's protocol for the management of the third stage of labour to recommend Syntometrine, in preference to oxytocin alone, for women being induced or augmented. We set out to assess the impact of the protocol change on the PPH rate. MATERIALS AND METHODS: A random sample of 1200 women who had a singleton, term vaginal birth before and after the protocol change was taken. Exclusion criteria were then applied to match PPH risk status. Using a quasi-experimental study design, PPH rates were compared between women who had received oxytocin or Syntometrine for third stage management. RESULTS: Five hundred and forty-nine women received oxytocin prior to the protocol change and were compared with 333 women who received Syntometrine after protocol change. There was no difference in the PPH rate with respect to uterotonic used (P = 0.9). There was no evidence of an interaction between labour type, third stage uterotonic and PPH (P = 0.4). PPH rates were lowest for women who laboured spontaneously and received Syntometrine (19% oxytocin, 14% Syntometrine). The PPH rate was unchanged by uterotonic in women whose labour was augmented (34% for both). PPH was more common in women being induced who received Syntometrine (22% oxytocin, 27% Syntometrine). None of these differences were statistically significant. CONCLUSION: Compared to oxytocin, Syntometrine did not reduce the rate of PPH in women with augmented or induced labour. Other approaches to reducing PPH rates are required.

The effects of hydroxychloroquine on endothelial dysfunction.

Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-α and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-α and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-α induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia.

Obesity and pregnancy outcomes: Do the relationships differ by maternal region of birth? A retrospective cohort study.

BACKGROUND: We aimed to determine whether the association between obesity and a range of adverse maternal and perinatal outcomes differed in South Asian and Australian and New Zealand born women. METHODS: A retrospective cohort study of singleton births in South Asian (SA) and Australian/New Zealand (AUS/NZ) born women at an Australian hospital between 2009 and 2013. The interaction between maternal region of birth and obesity on a range of maternal and perinatal outcomes was assessed using multivariate logistic regression. RESULTS: Obesity was more strongly associated with gestational hypertension/Preeclampsia/HELLP and Gestational Diabetes Mellitus in AUS/NZ born women (p = 0.001 and p < 0.001, respectively for interaction) and was only associated with shoulder dystocia in SA born women (p = 0.006 for interaction). There was some evidence that obesity was more strongly related with admission to NICU/Special care nursery (SCN) (p = 0.06 for interaction) and any perinatal morbidity (p = 0.05 for interaction) in SA born women. CONCLUSIONS: Interventions targeted at reducing maternal obesity will have different impacts in SA compared to AUS/NZ born women.

Evaluating the Impact of Human Amnion Epithelial Cells on Angiogenesis.

The effects of human amnion epithelial cells (hAECs) on angiogenesis remain controversial. It is yet unknown if the presence of inflammation and/or gestational age of hAEC donors have an impact on angiogenesis. In this study, we examined the differences between term and preterm hAECs on angiogenesis in vitro and in vivo. Conditioned media from term hAECs induced the formation of longer huVEC tubules on Matrigel. Both term and preterm hAECs expressed VEGFA, PDGFB, ANGPT1, and FOXC1, which significantly increased after TNFα and IFNγ stimulation. In the presence of TNFα and IFNγ, coculture with term hAECs reduced gene transcription of Tie-2 and Foxc1 in huVECs, while coculture with preterm hAECs increased gene transcription of PDGFRα and PDGFRß and reduced gene transcription of FOXC1 in huVECs. In vivo assessment of angiogenesis using vWF immunostaining revealed that hAEC treatment decreased angiogenesis in a bleomycin model of lung fibrosis but increased angiogenesis in a neonatal model of hyperoxia-induced lung injury. In summary, our findings suggested that the impact of hAECs on angiogenesis may be influenced by the presence of inflammation and underlying pathology.

An Australian and New Zealand survey of practice of the use of oxytocin at elective caesarean section.

BACKGROUND: The use of oxytocin to prevent postpartum haemorrhage at elective caesarean section is largely based on evidence derived from vaginal births. Overseas studies indicate wide variation in practice with regard to specific doses of oxytocin administered at caesarean section. No such surveys have been undertaken in Australia or New Zealand. AIMS: To survey and report Australian and New Zealand practice regarding oxytocin administration at elective caesarean section. METHODS: A structured questionnaire was posted to Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists resident in Australia and New Zealand. RESULTS: One thousand five hundred and forty-seven questionnaires were distributed, of which 890 (58%) were returned. Of these, 700 Fellows, 600 from Australia and 100 from New Zealand, currently practiced obstetrics. Almost all Fellows, 686 (98%), reported that they administered an oxytocin bolus at elective caesarean section, most commonly 10 IU (n = 460) or 5 IU (n = 220). The choice of bolus dose was related to country, duration and type (private or public) of practice. A majority of Fellows, 683 (98%), used an additional oxytocin infusion, either routinely or selectively. A total of 68 different regimens were reported. The single most common regimen was 40 IU oxytocin in 1000 mL administered over four hours, used by 255 Fellows (37%). CONCLUSIONS: There are wide variations in the usage of oxytocin at elective caesarean section in Australia and New Zealand, most likely due to a lack of high level evidence to guide practice. Appropriately designed clinical trials are needed to provide evidence to support future practice.